Improved biodistribution of 125I-labeled anti-Tac disulfide- stabilized Fv fragment by blocking its binding to the α subunit of the interleukin 2 receptor in the circulation with preinjected humanized anti- Tac IgG

Hisataka Kobayashi, Tae M. Yoo, Debra Drumm, Meyoung-Kon Kim, Bao Fu Sun, Nhat Le, Keith O. Webber, Ira Pastan, Thomas A. Waldmann, Chang H. Paik, Jorge A. Carrasquillo

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13 Citations (Scopus)

Abstract

Animal studies using radiolabeled anti-Tac disulfide-stabilized Fv (dsFv) monoclonal antibody have shown formation of complexes in serum with the soluble α subunit of the interleukin 2 receptor α (sIL-2Rα). In this study, we improved the targeting of 125I-labeled anti-Tac dsFv to receptor-positive tumors in the presence of circulating receptor by preinjecting unlabeled humanized anti-Tac IgG antibody (HuTac IgG). We used mice bearing SP2/Tac tumor xenografts that express the IL-2Rα. A positive correlation was seen between tumor size and the concentration of circulating receptor. Tumor-bearing mice were injected with 125I-labeled anti-Tac dsFv (400 ng), either alone or 15 min after injection of HuTac IgG. The 125I- labeled anti-Tac dsFv formed high molecular weight complexes with the sIL- 2Rα. The fraction of the dsFv present in the complexes increased as tumor size increased (greater sIL-2Rα levels). The fractions of dsFv in the complexes were 9.9- to 11.6-fold higher when sIL-2Rα was not blocked with preinjected HuTac IgG. The administration of a 12-fold molar excess of HuTac IgG over sIL-2Rα resulted in >80% of the 125I activity present as the dsFv rather than in the complexes. Furthermore, the biodistribution of 125I-labeled anti-Tac dsFv was improved by blocking its binding to sIL- 2Rα by preinjecting HuTac IgG. Specifically, in the preinjected group, at 15 min postinjection, the 125I-labeled anti-Tac dsFv levels in tumor increased to 10.8% compared to 5.6% injected dose per gram in the non- preinjected group. In summary, our studies showed that preinjection of HuTac IgG can block the formation of complexes of circulating sIL-2Rα and 125I- labeled anti-Tac dsFv. This blockade is associated with faster blood clearance, higher tumor uptake, and greater tumor:nontumor ratios of the radiolabeled antibody fragment.

Original languageEnglish
Pages (from-to)1955-1961
Number of pages7
JournalCancer Research
Volume57
Issue number10
Publication statusPublished - 1997 May 15
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kobayashi, H., Yoo, T. M., Drumm, D., Kim, M-K., Sun, B. F., Le, N., Webber, K. O., Pastan, I., Waldmann, T. A., Paik, C. H., & Carrasquillo, J. A. (1997). Improved biodistribution of 125I-labeled anti-Tac disulfide- stabilized Fv fragment by blocking its binding to the α subunit of the interleukin 2 receptor in the circulation with preinjected humanized anti- Tac IgG. Cancer Research, 57(10), 1955-1961.